Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Imperial College London, London, UK.
Genes Immun. 2011 Mar;12(2):78-89. doi: 10.1038/gene.2010.61. Epub 2010 Dec 23.
Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. Wistar-Kyoto (WKY) rats show marked susceptibility to CRGN, whereas Lewis rats are resistant. Glomerular injury and crescent formation are macrophage dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterized Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change, <1% false discovery rate) for basal and LPS-stimulated macrophages. Moreover, we identified eight genes with differentially expressed alternatively spliced isoforms, by using an in-depth analysis at the probe level that allowed us to discard false positives owing to polymorphisms between the two rat strains. Pathway analysis identified several common linked pathways, enriched for differentially expressed genes, which affect macrophage activation. In summary, our results identify distinct macrophage transcriptome profiles between two rat strains that differ in susceptibility to glomerulonephritis, provide novel positional candidates for Crgn3-7 and define groups of genes that play a significant role in differential regulation of macrophage activity.
新月体性肾小球肾炎 (CRGN) 是导致快速进行性肾衰竭的主要原因，但其潜在的遗传基础尚不清楚。Wistar-Kyoto (WKY) 大鼠对 CRGN 表现出明显的易感性，而 Lewis 大鼠则具有抗性。肾小球损伤和新月体形成依赖于巨噬细胞，主要由七个数量性状位点 (Crgn1-7) 解释。在这里，我们使用微阵列分析在基础和脂多糖 (LPS) 刺激的巨噬细胞中，鉴定出位于使 WKY 大鼠易患 CRGN 的途径上的基因。我们在未表征的 Crgn3-7 上检测到 97 个新的定位候选基因。我们在基础和 LPS 刺激的巨噬细胞中鉴定出 10 个额外的次要效应基因，它们的表达在两个品系之间存在显著差异 (>5 倍变化，<1%假发现率)。此外，我们通过在探针水平进行深入分析，鉴定出 8 个具有差异表达的可变剪接异构体的基因，这使我们能够排除由于两个大鼠品系之间的多态性而导致的假阳性。通路分析确定了几个常见的连锁途径，这些途径富集了差异表达的基因，这些基因影响巨噬细胞的激活。总之，我们的结果确定了两种在肾小球肾炎易感性上存在差异的大鼠品系之间的独特巨噬细胞转录组图谱，为 Crgn3-7 提供了新的定位候选基因，并定义了在巨噬细胞活性差异调控中起重要作用的基因组。
